RORγ is a member of nuclear receptor (NR) superfamily of transcription factor. NR superfamily contains 48 members in humans and includes receptors for steroid hormones, thyroid hormone, various lipids, and oxysterols. NRs function as ligand-dependent transcription factors and share a modular domain structure (Mangelsdorf, D. J et al. Cell 83, 835-83, 1995) comprising N′-terminal AF1 (or A/B) and DNA-binding (DBD) domains, followed by C′-terminal ligand binding (LBD) and AF2 (or F) domain; both sides are joined by a flexible hinge region (D).
Many of the NRs, including ROR family members (RORα, RORβ and RORγ), do not have validated ligands and are called orphan nuclear receptors. RORγ is expressed as two isoforms due to alternative splicing from RORC gene. The shorter transcript called RORγt or RORγ2 lacks two exons at 5′-terminal. Unlike widely expressed RORγ in several tissues including the thymus, kidney, liver, and mussels, RORγt is expressed exclusively in immature CD4+CD8+ double positive thymocytes and in a population of lymphoid tissue inducers (LTi) of fetal lever. Among mature T cells, RORγt is expressed in IL-17 secreting T cell populations (eg. Th17, γδT cells etc). The highly conserved N′-DBD of RORγ(t) recognizing AGGTCA on DNA (RORE), while C′-terminal LBD contains 12 α-helices of which H3-H5 are important for co activator or co repressor interactions; H12 contains core motif LYKELF of AF2 domain. At resting stage, RORγt is localized in nucleus and upon ligand binding binds to DNA as monomer (Jetten, M., et al. Prog Nucleic acid Res Mol Biol 69, 205-247, 2001).
RORγt is the signature transcription factor for differentiation and function of IL-17 producing T Helper (Th17) cell lineage, a newly discovered subset of T-helper cell population. Th17 cells are major producer of IL-17A, IL-17F, IL-22, IL-21 proinflammatory cytokines, which have a major role in many of inflammatory and autoimmune diseases but not limited to psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowl diseases, COPD, Colitis, Crohhn's disease and asthma (Lock et al. Nat. Med. 8, 2002, 500-508; Tzartos et al. Am. J. Pathol, 172, 208, 146-155; Koteke et al. J clin. Invest, 103, 1999, 1345-1352; Kirkham et al. Arthritis Rheum, 54, 2006, 1122; Seiderer et al. Inflamm. Bowel Dis. 14, 208, 437-445; Wong et al. Clin. Exp. Immunol. 125, 2001, 177-183; Agache et al. Respir. Med. 104, 2010, 1131-1137. In murine models of these diseases, inhibition of IL-17 function by neutralizing antibodies or generic disruption of IL-17 or Il-17 receptors amelioraties the diseases course or clinical symptoms (Hu et al. Ann. N.Y. Acad Sci. 1217, 2011, 60-67).
There are recent evidences for role of Th17 in other autoimmune diseases like systemic lupus erythematosus, Behcet's syndrome, scleroderma, transplant rejection and asthma. Th17 cells cause major inflammatory response by direct as well as indirect methods, like neutrophil infiltration by IL-17, tissue damage, keratinocyte proliferation by IL-22 etc. Hence, small molecule antagonists of RORγt are expected to inhibit production of these pro-inflammatory cytokines and have broad potential as novel anti-inflammatory compounds Huang, Q., et al. Arthritis Rheumat 56, 2192-2201, 7, 2007; Kimura, A., et al. Internat Immunopharmacol 11, 319-322, 2011. RORγt inhibitors might be useful in diseases where increased levels of TH17 cells and/or elevated levels of IL-17, IL-22 and IL-23 in infectious disease like mucosal leishmaniasis and many more (Boaventura et al. Eur. J immunol. 40, 2010, 2830-2836; Hashimoto thyroiditis (Figuerovega et al. J. Clin. Endocrinol. Metab. 95, 2010, 953-962 and Kawasaki disease (Jie et al. Clin. Exp. Immunol. 162, 131-137, 2010). Mouse model of cancer showed relevance TH17 cells. Evidences suggest that the effector T cell subset is also involved in tumor immunology, thus giving a way to a new target for cancer therapy (Nat. rev. Immuno. 10, 248-256, 2010). The approach of targeting TH-17 cells also validate in clinical studies with several IL-17 antibodies for several autoimmune disorders.
Disrupting of RORγt in mice also attenuates disease progression or severity in animal models of autoimmunity and inflammation including experimental autoimmune encephalomyelitis (EAE), imiquimod induced psoriasis, colitis and allergic airway disease (Ivanov et al. cell, 126, 2006, 1121-1133; Young et al. Immunity, 28, 2008, 29-39; Pantelyushin et al. J. Clin Invest. 122, 2012, 2252-2256; Leppkes et al. Gastroentrology, 136, 2009, 257-267 and Tilley et al J. Immunol. 178, 2007, 3208-3218.
Several patent applications and publications describe the discovery of small molecule RORγt inhibitors like thiazoles in WO2012027965 and WO 2012/028100; benzoxazepins in WO 2011107248; amide compounds in WO 2011112263; indole and indazole amides in WO2012106995, WO2014026329 and WO2012064744; isooxazole in WO2012147916; sulfonamides and cyclic sulfonamides in WO2014009447 and WO2013092939; quinolines in WO2014062667; pyrimidine in WO2014062938; pyridine in WO2014125426.
No RORγt inhibitor has yet reached the marketing stage. Therefore, there remains a need for discovering novel RORγ inhibitors possessing desirable properties such as pharmacokinetic/pharmacodynamic and or physicochemical and/or other drug like profiles to advance into clinics.
Therefore, there is a strong need for novel small molecule RORγ modulators that will have potential clinical utility. These compounds will have medical applications in the disease area of inflammation, autoimmune disorder and cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, Sjögren's Syndrome, multiple sclerosis, inflammatory bowel disease, allergic diseases, infectious diseases affecting immune system, asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, transplant rejection, cancers, COPD and graft-versus-host disease.    WO2013131923, WO2013104598, WO2013030288, US20120029002 and US20100029653 disclose a compound represented by the formula:
Wherein each symbol is as defined in the specification, as useful in the treatment and/or prophylaxis of cardiovascular disorders.    US 20070043057 and US 20070015771 disclose a compound represented by the formula:

Wherein each symbol is as defined in the specification, as anticancer agents.
The present disclosure provides a series of novel bicyclic compounds characterized as RORγ inhibitors and their potential use in pathogenesis of diseases as medicament for the treatment of RORγ mediated diseases.